The production methods of peptide are generally divided into solid phase methods and liquid phase methods. The solid phase methods are advantageous since isolation and purification after reaction can be performed by only washing resin. However, they are associated with problems in that the reaction is essentially that of heterogeneous phases, reaction agents and reagents need to be used in excess to compensate for the low reactivity, and tracing of reaction and analysis of reaction product supported by carrier are difficult. On the other hand, the liquid phase method is advantage since it shows good reactivity, and intermediate peptide can be purified by extraction and washing, isolation and the like after condensation reaction. However, the method is associated with problems since the production step is complicated due to an extraction and washing step with a nonpolar organic solvent and an acidic or basic aqueous solution to remove residual reagents and/or byproducts in each step of coupling reaction and deprotection, and/or an isolation and purification step such as crystallization and the like, and the like.
In recent years, approaches to improve the problems of the aforementioned two methods have been ongoing.
Patent document 1 and non-patent document 1 each disclose a method using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol type compound as a protecting reagent of carboxyl group and the like. Patent documents 2-4 each disclose a 3,5-di(docosyloxy)benzyl alcohol type compound, a 2,4-di(docosyloxy)benzyl alcohol type compound, a trityl type compound and the like as protecting reagents. Using these protecting reagents, the reaction can be performed in a homogeneous liquid phase, a precipitate can be produced by changing the solvent composition after the reaction, which can be isolated and purified by filtration and washing alone. However, use of these protecting reagents is associated with problems in that a reaction solvent evaporation step for precipitation is required, a long time is necessary for a precipitate filtration step, and these protecting reagents are insoluble or slightly-soluble in acetate ester or toluene. Therefore, the methods disclosed in the above-mentioned documents are not entirely industrially universal methods.
Patent document 5 introduces an example of a peptide synthesis reaction using a 3,4,5-tris(n-octadecyloxy)benzyl alcohol type compound as a protecting reagent. However, the document only discloses an example of a specific layer-separating separation of organic solvents under dilute conditions, and this example is not entirely an industrially universal method.